Nanopores sound hopelessly small, but Vincent Tabard-Cossa says they will someday be used as diagnostic tools. The tiny, nanometer-sized holes they make in a thin membrane allow researchers to capture and study single molecules, including DNA.

The creativity in developing nanopores for biosensing is in the type of detector used, Tabard-Cossa says. That, he adds, is where nanopores get their sensitivity. While a postdoc at the University of British Columbia in Andre Marziali’s lab, Tabard-Cossa and his colleagues developed a method called nanopore force spectroscopy that has “tremendous specificity” for molecular recognition, he says. He likens it to the hybridization process on a microarray, but adds that it not only reports the binding, but also measures the strength of the bond. “By measuring the time it takes to break the bond between the probe and the target at a particular force, this provides us with information about the dissociation energy of the two molecules,” Tabard-Cossa says. “And the dissociation energy, in turn, provides information about the sequence of the nucleotides.”

This detection, he adds, can then be carried out in parallel. “We can now repeat all these single-molecule experiments with hundreds of nanopores in parallel — or what would be best thousands or hundred of thousands — and get extremely fast measurement times,” he says. “Ultimately [we could] perform SNP detection from unamplified genomic DNA within minutes after collecting a blood sample. We haven’t really gone that far but [we are] working this way.”

Now at Stanford, Tabard-Cossa is focusing on embedding electrical probes into nanopore walls to sense molecules, particularly DNA, electrostatically. “We are using a unique sensing mechanism that is based on this partial suppression of ionic shielding in high electric fields and that’s due to the presence of electrodiffusion and relaxation effects,” he says. “It means that molecules are not shielded anymore by their ionic clouds, so that you can detect them pretty far away.”

Right now, his sensor can reach down to the scale of hundreds of electrons, which translates to a hundred-nucleotide-level sensitivity. Here, he is limited by electronics and the noise they detect. “Right now, we are not fully integrated, meaning our electronics are not as close as possible on our nanopore detector,” Tabard-Cossa says. “If we keep combining our integration, and really make streamlined electronics on our nanopore device, then we can reach tens of electrons, if not single-electron resolution.”

Looking ahead

Tabard-Cossa says there is still a bit of physics to learn, and, depending on how that pans out, accurate nanopore-based sequencing technology could be viable as soon as five years from now or as far away as 10. “There’s a lot of unexplored physics at this scale,” he says. “We still need to make great advances not only in nanopore fabrication … but also to understand how matter interacts. How does DNA interact with synthetic devices?”

Publications of note

Tabard-Cossa was the first author on a 2007 paper appearing in Nanotechnology that discusses noise in solid-state nanopores. He and his colleagues reduced the dielectric noise by curing the nanopore chip with polydimethylsiloxane. This improved the performance and yielded “an unprecedented signal-to-noise ratio when observing dsDNA translocation events and ssDNA probe capture for force spectroscopy applications,” they report in the paper abstract.

And the Nobel goes to…

Tabard-Cossa says that if he were to win the Nobel Prize, he’d have to share it with an army of people. He hopes that the prize would be for developing single-molecule detectors to be used in cheap and fast diagnostics that drive down the cost of healthcare.